Knee Osteoarthritis
Conditions
Keywords
Osteoarthritis, Knee, CRx-102, prednisolone, dipyridamole, CombinatoRx, WOMAC
Brief summary
CRx-102 is a synergistic combination drug candidate containing the cardiovascular drug dipyridamole and a very low dose of the glucocorticoid prednisolone. CRx-102 is believed to work through a novel mechanism of action in which dipyridamole selectively amplifies the anti-inflammatory and immunomodulatory activities of the glucocorticoid without replicating the dose-dependent adverse effects. CRx-102 has been associated with clinical benefit in proof of concept studies in subjects with hand OA and RA. This is the first study to explore the efficacy of CRx-102 in knee OA. It is considered a dose-finding study and will also compare the potential benefits of CRx-102 treatment to both prednisolone administered alone and to placebo in this indication.
Interventions
DRUGCRx-102 (2.7/90)
CRx-102 dose 1
DRUGPrednisolone
Prednisolone
DRUGPlacebo
Placebo
CRx-102 dose 2
CRx-102 dose 3
Sponsors
Zalicus
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject must voluntarily give written informed consent * Subject must be ≥ 40 years of age * Knee pain for at least 6 months requiring NSAIDs or Coxibs for analgesia on the majority of days (≥ 15 days) during the preceding month * WOMAC pain score when walking on a flat surface (question #1) between 30-80 mm at Screening with at least a 10 mm increase following NSAID or Coxib discontinuation during the Screening period * Radiographic evidence of knee OA (Kellgren-Lawrence grade 2 or 3) * Functional class I, II, or III according to the American Rheumatism Association * Subject willing to take a multivitamin or the equivalent of at least 400 IU vitamin D and the equivalent of at least 1000 mg of elemental calcium daily
Exclusion criteria
* Predominant patellofemoral disease or clinically significant trauma to index knee * History of clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, osteoporotic and/or other major disease * History of malignancy within the past 10 years (except for excised or treated basal cell or fewer than 3 squamous cell skin carcinomas) * History of lymphoma or chronic leukemia * Moles or lesions that are currently undiagnosed, but are suspicious for malignancy * Surgery within the previous 3 months (except for minor dental, and/or cosmetic procedures) * History of drug or alcohol abuse (as defined by the Investigator) * History of bleeding disorder * History of GI bleeding within 5 years of Screening * History of severe migraines or headaches * History of glaucoma * Visually compromising cataract * Active diabetic retinopathy * History of osteoporotic fracture * History of opportunistic infection * Serious local infection (e.g., cellulitis, abscess) or systemic infection (e.g., septicemia) within 3 months prior to Screening * Fever or symptomatic viral or bacterial infection within 2 weeks prior to Screening * Positive for hepatitis C (HCV) antibody * Positive for hepatitis B surface antigen (HBsAg) * Known positive history for human immunodeficiency virus (HIV) antibody * Surgery on the index knee within 1 year of Screening * History of hypersensitivity to steroids or dipyridamole * Treatment with oral, intramuscular, or intravenous glucocorticoids within 6 weeks prior to Screening; intra-articular glucocorticoids within 10 weeks prior to Screening; inhaled glucocorticoid is permitted * Treatment with injectable hyaluronic acid within 3 months of Screening * Treatment with another investigational drug, investigational device, or approved therapy for investigational use within 30 days prior to Screening * Treatment with NSAIDs (oral or topical), Coxibs or topical capsaicin * Treatment with anticoagulants including: dipyridamole, warfarin, clopidogrel, ticlopidine, or ASA \> 81 mg per day * Treatment with any concomitant medications that have not been at a stable dose for at least 28 days prior to Screening * Treatment for osteoporosis such as bisphosphonates (e.g., Fosamax®, Actonel®), or teriparatide (e.g., Forteo®), or calcitonin (e.g., Miacalcin, Calcimar) must be at stable dosages for at least 3 months prior to Screening * ALT or AST laboratory values \>1.5 X the ULN * HgbA1c value of \>7.0% * Current enrollment in any other study with investigational drug or device * Female subject who is pregnant or lactating * Unwilling or unable to comply with the requirements of this protocol, including the presence of any condition (physical, mental, or social) that is likely to affect the subject's return for follow-up visits on schedule * Other unspecified reasons that, in the opinion of the Investigator or sponsor make the subject unsuitable for enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Day 98 Using the WOMAC Pain Question #1 | Baseline to Day 98 | The WOMAC Index is a validated, 24-question self-administered assessment of three dimensions of pain, stiffness, and physical function for subjects with knee or hip OA. The WOMAC pain question #1 asks subjects to think about the pain you felt in your (study joint) caused by your arthritis during the last 48 hours when walking on a flat surface. This is a visual analog scale (VAS) where the subject indicates pain severity by making a mark through a 100 mm horizontal line with No Pain on the left (0 mm) and Extreme Pain on the right (100 mm). The distance between the left end of the scale and the subject's mark is measured in millimeters. Lower values represent a better outcome. |
Secondary
| Measure | Time frame |
|---|---|
| To Assess the Efficacy of the CRx-102 Compared to Placebo on the Change From Baseline to Day 98 Using the Full WOMAC Pain, Stiffness, Physical Function Parameters, and Patient Global Assessment VAS. | Day 98 |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CRx-102 (2.7/90 mg) CRx-102 (Prednisolone 2.7 mg + Dipyridamole 90 mg)
prednisolone + dipyridamole: CRx-102 (Dose 1), CRx-102 (Dose 2), CRx-102 (Dose 3) | 56 |
| CRx-102 (2.7/180 mg) CRx-102 Dose 2 (2.7 mg prednisolone + 180 mg dipyridamole)
prednisolone + dipyridamole: CRx-102 (Dose 1), CRx-102 (Dose 2), CRx-102 (Dose 3) | 54 |
| CRx-102 (2.7/360 mg) CRx-102 Dose 3 (2.7 mg prednisolone + 360 mg dipyridamole)
prednisolone + dipyridamole: CRx-102 (Dose 1), CRx-102 (Dose 2), CRx-102 (Dose 3) | 57 |
| Prednisolone Prednisolone 2.7 mg
Prednisolone: Prednisolone | 54 |
| Placebo Placebo
Placebo: Placebo | 58 |
| Total | 279 |
Baseline characteristics
| Characteristic | CRx-102 (2.7/90 mg) | CRx-102 (2.7/180 mg) | CRx-102 (2.7/360 mg) | Prednisolone | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 61.1 years STANDARD_DEVIATION 9.35 | 59.4 years STANDARD_DEVIATION 10.02 | 57.7 years STANDARD_DEVIATION 9.03 | 60.2 years STANDARD_DEVIATION 8.65 | 57.9 years STANDARD_DEVIATION 7.46 | 59.3 years STANDARD_DEVIATION 8.96 |
| Sex: Female, Male Female | 37 Participants | 33 Participants | 38 Participants | 30 Participants | 37 Participants | 175 Participants |
| Sex: Female, Male Male | 19 Participants | 21 Participants | 19 Participants | 24 Participants | 21 Participants | 104 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 19 / 58 | 26 / 54 | 29 / 56 | 29 / 54 | 40 / 57 |
| serious Total, serious adverse events | 1 / 58 | 1 / 54 | 2 / 56 | 1 / 54 | 1 / 57 |
Outcome results
Primary
Change From Baseline to Day 98 Using the WOMAC Pain Question #1
The WOMAC Index is a validated, 24-question self-administered assessment of three dimensions of pain, stiffness, and physical function for subjects with knee or hip OA. The WOMAC pain question #1 asks subjects to think about the pain you felt in your (study joint) caused by your arthritis during the last 48 hours when walking on a flat surface. This is a visual analog scale (VAS) where the subject indicates pain severity by making a mark through a 100 mm horizontal line with No Pain on the left (0 mm) and Extreme Pain on the right (100 mm). The distance between the left end of the scale and the subject's mark is measured in millimeters. Lower values represent a better outcome.
Time frame: Baseline to Day 98
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CRx-102 (2.7/90 mg) | Change From Baseline to Day 98 Using the WOMAC Pain Question #1 | -32.4 millimeters | Standard Deviation 27.07 |
| CRx-102 (2.7/180 mg) | Change From Baseline to Day 98 Using the WOMAC Pain Question #1 | -33.2 millimeters | Standard Deviation 32.02 |
| CRx-102 (2.7/360 mg) | Change From Baseline to Day 98 Using the WOMAC Pain Question #1 | -37.3 millimeters | Standard Deviation 33.07 |
| Prednisolone | Change From Baseline to Day 98 Using the WOMAC Pain Question #1 | -40.4 millimeters | Standard Deviation 30.04 |
| Placebo | Change From Baseline to Day 98 Using the WOMAC Pain Question #1 | -34.6 millimeters | Standard Deviation 27.11 |
Secondary
To Assess the Efficacy of the CRx-102 Compared to Placebo on the Change From Baseline to Day 98 Using the Full WOMAC Pain, Stiffness, Physical Function Parameters, and Patient Global Assessment VAS.
Time frame: Day 98